Yeah, you should check this out:

The authors started off by looking at the genes expressed in muscle biopsies from muscles undergoing atrophy, and they made note of which genes had high or low expression. Then, they screened 1300+ compounds for any that could (basically) decrease the high genes and increase the low genes, the idea being that any compound that could reverse the gene expression in muscle atrophy might be a good treatment. And they were right.

Ursolic acid

The screen identified ursolic acid, a compound found in large quantities in apple peels, as the only potential inhibitor of muscle atrophy. So the researchers injected ursolic acid into mice with atrophic muscles, which stopped muscle loss and increased muscle weight by 7%. Seven percent might not sound like a lot, but it is, considering that, again, this is the first compound shown to stop muscle loss at all. A 7% increase in muscle weight in a 180 lb man with typical muscle mass would mean a gain of over 5 pounds of muscle.

Ursolic acid diet shrinks fat cells

Things got even more interesting when normal mice were put on a diet with 0.27% ursolic acid: muscles got bigger and significantly stronger, blood levels of fat and cholesterol decreased, and fat cells shrank considerably, thus reducing fat weight significantly (see for yourself in a figure from the article, left). This is all in addition to the lowered blood sugar in fasting mice who received ursolic acid injections. To make things even better, the authors were able to identify genes that were increased or decreased by treatment, and that were probably responsible for these effects.

In my opinion, these scientists stumbled across something even greater than what they hoped to find. Their data on ursolic acid suggests its usefulness in treating everything from muscle atrophy to obesity to metabolic syndrome to type 2 diabetes. Not even mentioned in this paper is the work that has previously shown the ability of ursolic acid to inhibit cancer cells and Alzheimer’s proteins.

Okay, I’m impressed. What doesn’t ursolic acid do? Seems like it could be a future wonder drug! I’m very interested to see what scientists will try with this compound next…

Have a nerdy weekend!

Kunkel SD, Suneja M, Ebert SM, Bongers KS, Fox DK, Malmberg SE, Alipour F, Shields RK, & Adams CM (2011). mRNA expression signatures of human skeletal muscle atrophy identify a natural compound that increases muscle mass. Cell metabolism, 13 (6), 627-38 PMID: 21641545

Shishodia S, Majumdar S, Banerjee S, & Aggarwal BB (2003). Ursolic acid inhibits nuclear factor-kappaB activation induced by carcinogenic agents through suppression of IkappaBalpha kinase and p65 phosphorylation: correlation with down-regulation of cyclooxygenase 2, matrix metalloproteinase 9, and cyclin D1. Cancer research, 63 (15), 4375-83 PMID: 12907607

Pathak AK, Bhutani M, Nair AS, Ahn KS, Chakraborty A, Kadara H, Guha S, Sethi G, & Aggarwal BB (2007). Ursolic acid inhibits STAT3 activation pathway leading to suppression of proliferation and chemosensitization of human multiple myeloma cells. Molecular cancer research : MCR, 5 (9), 943-55 PMID: 17855663

Wilkinson K, Boyd JD, Glicksman M, Moore KJ, & El Khoury J (2011). A high-content drug screen identifies ursolic acid as an inhibitor of amyloid-{beta} interactions with its receptor CD36. The Journal of biological chemistry PMID: 21835916

However, despite the benefits of anti-retroviral therapies against AIDS progression, the authors of this paper suggest that these same therapies are associated with the accumulation of mutations in the energy-producing mitochondria of cells — the same kinds of mutations that would naturally occur later in life as part of the aging process.

Title: Mitochondrial aging is accelerated by anti-retroviral therapy through the clonal expansion of mtDNA mutations

Authors: Brendan A. I. Payne, Ian J. Wilson, Charlotte A. Hateley, Rita Horvath, Mauro Santibanez-Koref, David C. Samuels, D. Ashley Price & Patrick F. Chinnery

Date of publication: June 26, 2011

Direct Link: http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.863.html

PMID: 21706004

Abstract: In the past few years it has been reported that people who are successfully treated with anti-retroviral therapies against HIV infection show signs of premature aging and ultimately experience progressive multi-organ disease. By performing extensive DNA sequencing and analysis on the single-cell level, these researchers found that patients who had used anti-retroviral drugs had increased mutations in their mitochondria (a cellular subcompartment for generating energy). Because the patients also exhibited premature aging, these results suggest that mitochondrial DNA mutations may play a role in the normal aging process that we all experience.

Methods: The authors obtained frozen muscle biopsy samples from HIV-positive patients treated with or without retroviral drugs and looked for abnormalities in mitochondrial proteins. Also, extremely sensitive sequencing of mitochondrial DNA was used to characterize the mutations in that DNA.

Results: Thirty-three HIV-positive adults under the age of 50 provided muscle biopsies for this work. The authors were looking at a mitochondrial protein that is used by the mitochondria to make energy - the more abnormal the protein, the less healthy the mitochondria. In the patients who had not received anti-retroviral drugs, the amount of this protein, cytochrome c oxidase (COX), was the same as in an HIV-negative control population. However, HIV-positive patients who had received anti-retroviral drugs showed a significant reduction in the amount of COX protein – the protein levels were comparable to or even more reduced than what would be found in the elderly. DNA was analyzed in single cells from these patients and the cells deficient in COX protein showed significantly more deletions in the mitochondrial DNA, including deletions commonly seen in healthy elderly adults (recall, though, that the patients in this research are less than 50-years-old). Also, the total amount of mitochondrial DNA in COX-deficient cells was significantly increased, and the authors propose a theory of “clonal expansion” in these patients: some of the mutated DNA underwent rapid replication, propagating the mutation until a high proportion of the total DNA was mutated.

Bottom line: This research makes two points that I think are highly relevant for disease and health: 1) The knowledge that some anti-retroviral therapies induce a premature aging effect is something that every HIV-positive individual has a right to know before beginning those treatments. Also, now that a potential mechanism has been described for how these drugs may be having an aging effect, researchers have the option to develop combination therapies to stop HIV virus replication while also preventing mitochondrial DNA mutations from accumulating. 2) This work supports the idea that mitochondrial DNA mutations may be part of what causes aging in healthy people, rather than a consequence of the aging process itself.

Payne BA, Wilson IJ, Hateley CA, Horvath R, Santibanez-Koref M, Samuels DC, Price DA, & Chinnery PF (2011). Mitochondrial aging is accelerated by anti-retroviral therapy through the clonal expansion of mtDNA mutations. Nature genetics PMID: 21706004